An FGF (fibroblast growth factor) is known as a growth factor for controlling a variety of physiological functions such as cell growth, cell migration, cellular infiltration, cell survival, differential induction, wound healing and angiogenesis.
The FGF controls the various physiological functions via FGF receptors (FGFRs: FGFR1, FGFR2, FGFR3 and FGFR4), that is, receptor tyrosine kinases. Each FGFR includes three types of domains of an extracellular domain, a transmembrane domain and an intracellular tyrosine kinase domain. When an FGF binds to the extracellular domain of an FGFR, a dimer of the receptor is formed. Thereafter, the intracellular tyrosine kinase is activated, and then, an intracellular signal is transmitted mainly via a MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) pathway or a PI3K (phosphatidylinositol 3-kinase)/Akt pathway.
Meanwhile, it has been reported that various cancers such as breast cancer, bladder cancer, EMS (8p11 myeloproliferative syndrome), stomach cancer, endometrial cancer and prostatic cancer are caused as a result of induction of FGF/FGFR signal abnormality accompanying FGF production enhancement, FGFR gene amplification, FGFR overexpression, FGFR fusion protein production, FGFR mutation and the like (Non Patent Literature 1). Furthermore, the following have been reported as cancers accompanied by the FGF/FGFR signal abnormality: Non-small-cell lung carcinoma, small-cell lung carcinoma, ovarian cancer, sarcoma, colon cancer, melanoma, glioblastoma, astrocytoma, and head and neck cancer (Non Patent Literatures 2 and 3), thyroid cancer (Non Patent Literature 4), pancreatic cancer (Non Patent Literatures 5 and 6), liver cancer (Non Patent Literature 7), skin cancer (Non Patent Literature 8), kidney cancer (Non Patent Literature 9), and lung squamous cell carcinoma and the like (Non Patent Literatures 10, 11, and 12).
Besides, the FGF/FGFR signal is one of main angiogenic signals in endothelial cells along with a VEGF (vascular endothelial growth factor)/KDR (kinase-insert domain-containing receptor) signal, and is reported to be involved in the interaction between cancer stromal cells (fibroblasts) and cancer cells (Non Patent Literature 1).
Accordingly, an FGFR inhibitor targeting an FGF/FGFR signal is expected to work as an antitumor drug, against cancers accompanied by the FGF/FGFR signal abnormality, based on its inhibitory action against the signal abnormality and its inhibitory action against the angiogenic signal. Recently, a selective FGFR inhibitor regarded to be insusceptible to be affected by a confronting effect of another signal, such as a selective FGFR inhibitor against FGFR1, FGFR2 or FGFR3, which is obviously different in the structure from a compound of the present invention, has been reported. In the development as an antitumor drug for humans, however, the selective FGFR inhibitor falls behind an antitumor drug simultaneously targeting both the FGF/FGFR signal and the VEGF/KDR signal, and has not been put on the market yet (Non Patent Literatures 13 and 14; Patent Literatures 1 and 2). Patent Literature 3 discloses pyrimidine derivatives but does not disclose an inhibitory action against the signal abnormality of the FGF/FGFR signal. Patent Literature 4 discloses pyridine derivatives or pyrimidine derivatives that inhibit angiogenesis induced by the VEGF and the FGF. None of these literatures, however, discloses the compounds of the present invention.